Catheters play critical roles in the administration of chemotherapy, antibiotics, blood, blood products and total parenteral nutrition essential for the successful treatment of many chronic afflictions. Recent advances in catheter technology have enabled their explosive growth in nephrology (hemodialysis catheters) and inpatient interventions (peripherally inserted catheters).
Unfortunately, the hydrophobic catheter surface has a very high potential of allowing microbial colonization that lead to serious and often life-threatening complications, particularly nosocomial infections. To counter this risk, catheter insertion sites are maintained scrupulously clean, which, while reducing the probability of infection cannot completely eliminate infections that significantly increase patient morbidity and mortality. Current treatments to prevent catheter-related infections rely primarily on the use of antimicrobial loaded coatings. However, the tradeoffs between thin and thick coatings severely limits the performance of these powerful coatings, since thin coatings only have limited antibacterial life, while thick coatings may last longer, but are far more susceptible to cracking, peeling and flaking-off
Many approaches have been studied to reduce the incidence of bacterial infections associated with the use of indwelling catheters and trans-dermal implanted devices, but none have met with more than success for limited periods of time. Such infections include nosocomial infections, which are those resulting from treatment in a hospital or a healthcare service unit, but secondary to the patient's original condition. Infections are considered nosocomial if they first appear 48 hours or more after hospital admission or within 30 days after discharge. By way of background, the term “nosocomial” derives from the Greek word nosokomeion (νοσοκομε{acute over (ι)}ον) meaning hospital (nosos=disease, komeo=to take care of).
Nosocomial infections are even more alarming in the 21st century as antibiotic resistance spreads. Reasons why nosocomial infections are so common include:
Catheter insertions bypass the body's natural protective barriers;
Hospitals house large numbers of people who are sick and whose immune systems are often in a weakened state;
Increased use of outpatient treatment means that people who are in the hospital are sicker on average; and
Routine use of anti-microbial agents in hospitals creates selection pressure for the emergence of resistant strains.
In the United States, it has been estimated that as many as one hospital patient in ten acquires a nosocomial infection, or 2 million patients per year. Estimates of the annual systemic cost resulting from such infections range from $4.5 billion to $11 billion. Nosocomial infections contributed to 88,000 deaths in the U.S. in 1995.
The risk of contracting an infection in a clinical setting is increasing every year, and the types and virulent nature of such infections continues to rise. Due, in part to the loosening of import restrictions into the U.S. under the North American Free Trade Agreement (NAFTA), as well as widespread international air travel, eco-tourism to exotic third-world forests and islands, and massive migration of third-world peoples to Europe and America, hosts of exotic diseases that were once isolated to small areas of the planet are now finding their way into U.S. and European hospitals. Eradicated for almost a century, malaria is once again returning to the U.S, and the exotic and deadly Ebola virus has broken out in a lab in Maryland. Shigella (which causes dysentery) was practically unheard of in America before 1990, but it is now being spread from contaminated fruits and vegetables imported into the U.S. under the auspice of the NAFTA treaty, and is now routinely seen at clinics in California.
Of potentially greater concern is that many common strains of microorganisms have become increasingly resistant to a wide range of antibiotics (due to incomplete kills and simple natural selection). Many strains must be treated with one or two “last-resort” antibiotics and new compounds must be continually developed to combat these evolving strains. By way of example, some common (and dangerous) germs such as Staph aureus (found especially in hospitals) are now known to be resistant to all but one antibiotic-vancomycin—and soon are expected to be vancomycin-resistant as well. According to the Centers for Disease control, in 1992, 13,300 hospital patients died [in the U.S.] of bacterial infections that resisted the antibiotics administered to fight them.
Generally, antibacterial agents inhibit or kill bacterial cells by attacking one of the bacterium's structures or processes. Common targets are the bacterium's outer shell (called the “cell wall”) and the bacterium's intracellular processes that normally help the bacterium grow and reproduce. However, since a particular antibiotic typically attacks one or a limited number of cellular targets, any bacteria with a resistance to that antibiotic's killing mechanism could potentially survive and repopulate the bacterial colony. Over time, these bacteria could make resistance or immunity to this antibiotic widespread.
Silver, platinum and gold, which are elements of the noble metals group, have long been known to have medicinal properties. For example, platinum is the primary active ingredient in cisplatin, a prominent cancer drug. Similarly, gold is the active agent in some treatments for rheumatoid arthritis. More particularly, unlike its heavy metal counterparts, silver (atomic symbol Ag) with atomic element number 47 and an atomic weight of 108, is surprisingly non-toxic to humans and animals, and has a long history of successful medical and public health use dating back 6000 years. Also, unlike antibiotics, silver has been shown to simultaneously attack several targets in the bacterial cell and therefore it is less likely that bacteria would become resistant to all of these killing mechanisms and create a new silver-resistant strain of bacteria. This may be the reason that bacterial resistance to silver has not been widely observed despite its centuries-long use. This can be particularly important in hospitals, nursing homes and other healthcare institutions where patients are at risk of developing infections.
By way of further background, from 1900 to the beginning of the modern antibiotic era—circa 1940 with the introduction of sulfa drugs—silver and its ionic and colloidal compounds (silver nitrate, for example) was one of the mainstays of medical practice in Europe and America. Various forms of silver were used to treat literally hundreds of ailments: lung infections such as pneumonia, tuberculosis and pleurisy; sexual diseases such as gonorrhea and syphilis; skin conditions such as cuts, wounds, leg ulcers, pustular eczema, impetigo and boils; acute meningitis and epidemic cerebro-spinal meningitis; infectious diseases such as Mediterranean fever, erysipelas, cystitis, typhus, typhoid fever, and tonsillitis; eye disorders such as dacryocystitis, corneal ulcers, conjunctivitis and blepharitis; and various forms of septicemia, including puerperal fever, peritonitis and post-abortion septicemia. An even larger list of the published medical uses for silver in Europe and America exists between 1900-1940.
Sparsely-soluble silver salts are composed of large microcrystals, usually several microns in diameter or greater. These microcrystals dissolve extremely slowly, thereby limiting the rate and amount of silver ion released over time. By converting the salt's microscaled structure into an atomically nanoscaled structure, it tremendously increases the surface area, thus enhancing silver ion release and efficacy characteristics and thereby making it a more potent antimicrobial agent.
The provision of silver in a releasable form for use in an anti-microbial application is discussed, for example, in U.S. Pat. No. 6,821,936, entitled TEXTILES HAVING A WASH-DURABLE SILVER-ION BASED ANTIMICROBIAL TOPICAL TREATMENT, by David E. Green, et al., the teachings of which are expressly incorporated herein by reference. This patent provided a coating of an anti-microbial silver-salt-based treatment to fabric threads to resist the build-up of bacteria on a fabric. While this approach may be effective for fabrics, it and other silver-based solutions have certain drawbacks when applied to catheters and other invasive devices. First, when a coating is applied, for example to the lumen or exterior of a catheter, it changes the diameter of that catheter. The insertion of a guidewire, syringe tip or other close-conforming structure will tend to abrade the anti-microbial coating, again exposing the underlying, unprotected surface of the catheter/device. In addition these coatings are either designed to last long term, with very few silver atoms/ions released to the environment by the use of sparingly soluble silver compounds, or release all of their exposed soluble silver salt very quickly. This is because they are not adapted to exist within an implanted environment, where there is a constant source of new bacterial infiltration via the open wound channel. Also, because the coatings are relatively thin, they exhaust the available supply of silver salt (which is exposed at the coating surface) in a relatively short time.
It is, thus, desirable to provide a structural polymer, for which the implanted and exposed portion of the device is constructed, that contains the anti-microbial silver compound as an integrated part of its composition. However, the creation of a structural material that contains an embedded supply of silver is not trivial. The embedded silver may either release too slowly, or not at all if the material is not sufficiently hydrophilic. A hydrophilic material allows the needed ion exchange via interaction of the material with adjacent bodily fluids/water. Absent infiltration of water, deeper embedded silver will never have the chance to release, and only the material's surface silver is released. However, if the material is too hydrophilic, it may not exhibit the necessary structural strength to act as an invasive or implanted device or the material may undesirably swell as it absorbs bodily fluids causing the device to fall outside needed size tolerances. It is also not trivial to provide a material with the proper degree of hydrophilicity, while maintaining desired structural characteristics, and releasing silver at a desired rate. This goal typically calls for a polymer blend, and most polymers do not blend well—if at all. Adding a silver-containing compound only complicates the blending. Moreover, while some silver compounds may be blendable, industry often desires that the resulting device be clear or translucent and typically uncolored. Many silver containing compounds exhibit dark and/or undesired colors upon heating or exposure to light.
The challenge of developing a structural polymer is further complicated by a desired to quickly treat any existing infections or the large initial introduction of bacteria when inserting a device with a large, short-time-released dose of silver, and then providing a lower, continuing dose to ward off any re-infection. Accordingly it is desirable to provide a silver-compound-containing material that satisfies all of these often-competing goals.